8-Triazolylpurines: Towards Fluorescent Inhibitors of the MDM2/p53 Interaction

PLoS One. 2015 May 5;10(5):e0124423. doi: 10.1371/journal.pone.0124423. eCollection 2015.


Small molecule nonpeptidic mimics of α-helices are widely recognised as protein-protein interaction (PPIs) inhibitors. Protein-protein interactions mediate virtually all important regulatory pathways in a cell, and the ability to control and modulate PPIs is therefore of great significance to basic biology, where controlled disruption of protein networks is key to understanding network connectivity and function. We have designed and synthesised two series of 2,6,9-substituted 8-triazolylpurines as α-helix mimetics. The first series was designed based on low energy conformations but did not display any biological activity in a biochemical fluorescence polarisation assay targeting MDM2/p53. Although solution NMR conformation studies demonstrated that such molecules could mimic the topography of an α-helix, docking studies indicated that the same compounds were not optimal as inhibitors for the MDM2/p53 interaction. A new series of 8-triazolylpurines was designed based on a combination of docking studies and analysis of recently published inhibitors. The best compound displayed low micromolar inhibitory activity towards MDM2/p53 in a biochemical fluorescence polarisation assay. In order to evaluate the applicability of these compounds as biologically active and intrinsically fluorescent probes, their absorption/emission properties were measured. The compounds display fluorescent properties with quantum yields up to 50%.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Purines / chemistry*
  • Purines / pharmacology
  • Tumor Suppressor Protein p53 / metabolism


  • Purines
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2
  • purine

Grants and funding

This work was supported by the Swedish Research Council (project # 62120083533), the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children's Research Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.